Abstract: Corneal wound healing entails increases in proliferation and migration in the corneal epithelial cells through EGFR stimulation. We found that the transient receptor potential (TRP) vanilloid isoform 1 (TRPV1) induces such responses as well as increases in proinflammatory cytokine release through EGFR transactivation. We also detected functional cannabinoid receptor 1 (CB1) expression in human corneal epithelial cells (HCEC), which modulates TRPV1 mediated EGFR transactivation. Therefore, we hypothesize that crosstalk among TRPV1, CB1 and EGFR contributes to mediating corneal epithelial wound healing. Our three aims entail determining: 1) Signaling mechanisms eliciting TRPV1 crosstalk with CB1 receptors and EGFR transactivation in HCEC. 2) Signaling pathways leading to increases in cell migration, proliferation, and proinflammatory cytokine expression following TRPV1 transactivation of EGFR. 3) Impact in mice of TRPV1 knockout (TRPV1-/-) on corneal wound healing. The mechanisms eliciting CB1 modulation of TRPV1 and EGFR crosstalk will be characterized with pharmacological modulators and siRNA knockdown of different cell signaling intermediates. Our results showed that in TRPV1-/- mice injury induces much less inflammation and scarring and less translucence than in their wildtype counterpart. We will further determine the importance of TRPV1 function in eliciting the corneal wound healing responses in alkali-burned mice corneas by comparing wound healing responses in TRPV1-/- and wildtype mice. We will investigate whether or not a decline in corneal inflammatory cell infiltration or tissue chemoattractant expression accounts for less inflammation in the TRPV1-/- mice. The inflammatory cell responsiveness to proinflammatory cytokines will be assessed by performing bone marrow transplant experiments between the TRPV1-/- and wildtype mice and in vitro chemotaxis assay. Corneal inflammatory cell infiltration will be evaluated with immunohistochemistry. Such wound healing studies provide insight into receptor interactions mediating corneal epithelial renewal. They also may elucidate novel strategies for alleviating injury-induced corneal inflammation, discomfort and lessening scarring during wound healing.